We have shown that multiple myeloma is characterized by frequent (70%) chromosome translocations involving the immunoglobulin (Ig) genes and identified four recurrent loci that are commonly involved: 11q13, 6p21, 4p16, and 16q23. The translocations result in the juxtaposition of powerful Ig enhancers adjacent to oncogenes at these loci (cyclin D1, cyclin D3, FGFR3+MMSET, and c-maf, respectively), causing their ectopic and deregulated expression in plasma cells. Subsequent tumor progression occurs with deletion of chromosome 13, mutations of N or K ras, and secondary translocations of c-myc. The central hypothesis of this project is that genes selected by mutations are critical for the pathogenesis of myeloma and represent attractive targets for drug development. Approximately 25-35% of patients have IgH translocations that are not accounted for by the partners we have identified to date, and another 30% do not have a translocation. We propose to identify other genes selected by genetic mutation in myeloma, using a combination of gene expression analysis, comparative genomic hybridization, candidate gene analysis, and cloning of chromosome translocations. We propose to use both in vitro and in vivo model systems to validate these genes as appropriate targets for drug development, and develop assays to screen for drugs that inhibit the function of these targets. Finally we propose to introduce into clinical trials targeted agents showing promise in this pre-clinical evaluation The genetic evidence suggests that the IgH translocations are the primary event that leads to oncogenic transformation, making them a particularly attractive target. For all of this work we will first focus on FGFR3, and use it as a model to test this hypothesis. We will identify FGFR3 inhibitors by screening tyrosine kinase inhibitors entering clinical trials, and libraries of tyrosine kinase inhibitors for selective inhibition of FGFR3 auto-phosphorylation and downstream signals of FGFR3, STAT3 and MAPK phosphorylation. These studies will provide the framework for developing targeted therapies of myeloma, based upon the genetic abnormalities present in each patient. As with STI-571 in CML, we expect that targeting the transforming event may provide very effective therapy, and that targeting events related to progression may delay or prevent disease progression.